ArticleNature communications2016
Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS-p110 crosstalk.
Article in Nature communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 59 citations in OpenAlex.
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- Inhibition of HER2 signaling and breast cancer cell growth with a novel antibody targeting HER2 ECD III/IV.PloS one · 2026Article
- A nucleotide-independent, pan-RAS-targeted DARPin elicits anti-tumor activity in a multimodal manner.Molecular oncology · 2025Article
- Engineering bispecific HER2xVEGF designed ankyrin repeat proteins for targeted nanobiotechnology applications.Journal of nanobiotechnology · 2025Article
- Structural analysis of HER2-trastuzumab complex reveals receptor conformational adaptation.Science advances · 2025Article
- Mechanistic Insights into the Anticancer Potential ofPharmaceuticals (Basel, Switzerland) · 2025Article
- Interplay between lncRNAs and the PI3K/AKT signaling pathway in the progression of digestive system neoplasms (Review).International journal of molecular medicine · 2025Review
- Nano-strategies for Targeting Tumor-Associated Macrophages in Cancer immunotherapy.Journal of Cancer · 2025Review
- Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery.bioRxiv : the preprint server for biology · 2024Article
- Facile generation of biepitopic antibodies with intrinsic agonism for activating tumor necrosis factor receptors.Cell chemical biology · 2024Article
- Facile generation of biepitopic antibodies with intrinsic agonism for activating receptors in the tumor necrosis factor superfamily.bioRxiv : the preprint server for biology · 2023Article
- Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by reducing signaling activity through epitope selection.Communications biology · 2023Article
- Activity of osimertinib in a patient with stage IV non-small cell lung cancer harboringTranslational lung cancer research · 2023Article
- An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity.Nature communications · 2023Article
- A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells.Frontiers in immunology · 2023Article
- Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression.Signal transduction and targeted therapy · 2021Review
- Crystal structures of HER3 extracellular domain 4 in complex with the designed ankyrin-repeat protein D5.Acta crystallographica. Section F, Structural biology communications · 2021Article
- Apoptosis-inducing anti-HER2 agents operate through oligomerization-induced receptor immobilization.Communications biology · 2021Article
- Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action.Nature communications · 2021Article
- The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Compensatory mechanisms, such as relief of AKT-ErbB3-negative feedback, are known to desensitize ErbB2-dependent tumours to targeted therapy. Here we describe an adaptation mechanism leading to reactivation of the PI3K/AKT pathway during trastuzumab treatment, which occurs independently of ErbB3 re-phosphorylation. This signalling bypass of phospho-ErbB3 operates in ErbB2-overexpressing cells via RAS-PI3K crosstalk and is attributable to active ErbB2 homodimers. As demonstrated by dual blockade of ErbB2/RAS and ErbB3 by means of pharmacological inhibition, RNA interference or by specific protein binders obstructing the RAS-p110α interaction, both routes must be blocked to prevent reactivation of the PI3K/AKT pathway. Applying these general principles, we developed biparatopic designed ankyrin repeat proteins (DARPins) trapping ErbB2 in a dimerization-incompetent state, which entail pan-ErbB inhibition and a permanent OFF state in the oncogenic signalling, thereby triggering extensive apoptosis in ErbB2-addicted tumours. Thus, these novel insights into mechanisms underlying network robustness provide a guide for overcoming adaptation response to ErbB2/ErbB3-targeted therapy.
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